Treatment of a vancomycin-resistant Enterococcus faecium ventricular drain infection with quinupristin/dalfopristin and review of the literature.

Central nervous system infections involving vancomycin-resistant Enterococcus faecium (VREF) are infrequently described and pose significant therapeutic difficulties, because these organisms are intrinsically resistant to many antibiotics. We describe the use of intrathecal quinupristin/dalfopristin to treat a VREF-associated infection in a neuro--surgical patient.

Effects of the sheep-chewing louse (Damalinia ovis) on the epidermis of the Australian merino.

Frozen longitudinal skin sections taken from the dorsal thoraco-lumbar region of adult Merino sheep that were infested with the sheep-chewing louse were examined by light microscopy. The epidermis of infested sheep exhibited acanthosis due to hyperplasia of the stratum spinosum, and orthokeratosis. The thickness of the uncornified epidermis, the stratum corneum, and the sudanophilic region were significantly greater (P less than 0.005) than equivalent regions in louse-free Merinos and the results suggest that a positive correlation exists between the thickness of each region and the level of louse infestation. The results indicate that the variance in region thickness was greater in lousy than in louse-free sheep (P less than 0.005).

Structure of the epidermis of Australian Merino sheep over a 12-month period.

Light-microscopic examination of frozen sections of skin taken from the dorsal thoraco-lumbar region of Australian Merino sheep in winter revealed that the thickness of the epidermis plus a sudanophilic layer was 24.9 micron in the interfollicular region. The uncornified epidermis (10.9 micron) was separated from the sudanophilic layer (14.0 micron) by a thin stratum corneum. It was concluded that the bulk of the sudanophilic layer was emulsified sebum in which was embedded a disorganized collection of desquamated cornified cells. Although large variances were observed in the thickness of the uncornified epidermis and of the sudanophilic layers between sheep and both within the between blocks of tissue obtained from individual sheep, there were no strong seasonal effects on either epidermal structure or layer thickness over a 12-month period. These results suggest that the Australian Merino differs from Finnish Landrace X Dorset Horn ewes, which are reported to possess, at least in winter, a thicker uncornified epidermis and a thicker stratum corneum that could be divided into two zones and was uniformly permeated by lipid.

Effects of breed, season, temperature, and solvents on the permeability of frozen and reconstituted cattle skin to levamisole.

In vitro measurements have been made of the permeability of frozen and reconstituted cattle skins to levamisole. Breeds used were Red Poll cross, Hereford/Shorthorn cross, Hereford/Santa Gatrudis cross (or Brahman), Friesian (or Friesian/Jersey cross), and Hereford cattle killed in early fall, early summer, or winter. Inter- and intrabreed differences in skin permeability were small, but skin permeability in summer and fall was appreciably greater than in winter. Increases in skin temperature also increased skin permeability. The solvent properties of the skin toward neutral molecules appeared to be similar to those of water, suggesting that skin is a relatively polar barrier.

Conformational analysis of the ergot alkaloids ergotamine and ergotaminine.

Conformational analyses by 1H NMR and potential-energy calculations are reported for the ergot alkaloids ergotamine and ergotaminine, both as free bases and as the protonated species. In the neutral forms in CDCl3. two strong intramolecular hydrogen bonds fix the molecules in folded conformations, but the protonated species adopt a more extended conformation, with a single intramolecular hydrogen bond. Of the 24 alternative conformations available to ergotamine, the most likely biologically active species in environments with low dielectric constants, e.g., the presumed ergotamine binding site, is the folded, hydrogen-bonded conformation observed for the neutral molecule in CDCl3 solution.

A comparison of frozen and reconstituted cattle and human skin as barriers to drug penetration.

An in vitro study of the permeabilities of frozen and reconstituted cattle skin and human skin to levamisole was done. Cattle skin was 400 times more permeable to levamisole from an organic solvent (largely 2-ethoxyethanol) than was human skin. The diffusion coefficient value of levamisole in cattle skin and the partition coefficient value of levamisole from the organic solvent into the skin suggested that a relatively large amount of drug passed through skin appendages such as hair follicles or sweat/sebaceous ducts. Transcellular transport across the stratum corneum was rate-determining in human skin penetration.

N-hydroxymethyl derivatives of nitrogen heterocycles as possible prodrugs I: N-hydroxymethylation of uracils.

Solid samples of 1,3-dihydroxymethyluracil, 3-hydroxymethyl-1-methyluracil, and 1-hydroxymethyl-3-methyluracil were prepared, and their structures were confirmed by spectroscopic analysis. The thermodynamics and kinetics of the formation of N-hydroxymethylated uracils in aqueous formaldehyde solutions also were studied. The equilibrium constants for formation of N-1-hydroxymethyl derivatives were approximately twice those for formation of N-3-hydroxymethyl derivatives, and they were formed more rapidly throughout the pH 3--8 range. Substituents at C-5 of uracil had little effect on the thermodynamics of N-hydroxymethylation. The potential usefulness of N-hydroxymethyl compounds as prodrugs is discussed.

N-hydroxymethyl derivatives of nitrogen heterocycles as possible prodrugs II: possible prodrugs of allopurinol, glutethimide, and phenobarbital.

Solid samples of 1-hydroxymethyl- and 1,5-dihydroxymethylallopurinol, 1-hydroxymethylglutethimide, and 1-hydroxymethylphenobarbital were prepared, and equilibrium constants for their formation from formaldehyde and allopurinol, glutethimide, or phenobarbital were calculated. The N-hydroxymethyl derivatives had higher water solubilities and faster dissolution rates than the parent drugs, and they appear to be potentially useful as prodrugs.

Amino acid esters of phenols as prodrugs: synthesis and stability of glycine, beta-aspartic acid, and alpha-aspartic acid esters of p-acetamidophenol.

pH-rate profiles were calculated for the hydrolysis of the glycine (II), beta-aspartic acid (III), and alpha-aspartic acid (IV) esters of p-acetamidophenol (I) at 25 degrees and mu = 1.0 M. The hydrolysis of esters II and III occurred predominantly via intermolecular reactions involving water, hydroxide ion, and the various ionic forms of the substrates. The hydrolysis of ester IV occurred predominantly via intramolecular reactions. The catalytic effects of formate, acetate, and phosphate ions as well as of tromethamine on the degradation on ester II were similar to their effects on the hydrolysis of ethyl dichloroacetate. The efficient catalysis of the hydrolysis of ester II in bicarbonate buffers was consistent with a mechanism that involved carbon dioxide and the formation and decomposition of a carbamate intermediate.

Effect of caffeine on ergotamine absorption from rat small intestine.

The effect of caffeine on the absorption of ergotamine from the rat small intestine was studied. The results of a series of experiments showed that caffeine significantly enhanced absorption of ergotamine from solutions of pH 5.0 when both substances were in solution and when an intact blood supply was either absent (in vitro everted sac experiments) or present (in situ experiments). Caffeine did not appear to influence the absorption rate of ergotamine in situ experiments when the solution pH was 3.0. Isosorbide dinitrate, a vasodilator, enhanced ergotamine absorption when both substances were administered simultaneously into intestinal loops in situ. Isosorbide dinitrate probably exerts its effect by increasing blood flow to the intestine. The results are consistent with an hypothesis that the rate-determining step in ergotamine absorption is the transport of the drug from a lipid phase (GI membrane) into an aqueous phase (blood). Caffeine is thought to exert its rate-accelerating effect by increasing the water solubility of ergotamine neutral molecules.

Solubility and dissolution rate studies of ergotamine tartrate.

The solubility of ergotamine tartrate in aqueous solutions of tartaric acid, citric acid, hydrochloric acid, and caffeine and the dissolution rate of ergotamine tartrate in aqueous mixtures containing hydrochloric acid, caffeine, citric acid, or sodium acetate were studied. The Noyes-Whitney model of dissolution is useful for predicting the dissolution rate of ergotamine tartrate in most of the dissolution media. The relative slowness with which ergotamine chloride (a substance with low water solubility) precipitated when ergotamine tartrate was dissolved in 0.1 M HCl resulted in the solid dissolving faster in this medium than was predicted using the Noyes-Whitney equation.

N-Halo derivatives VI: Microbiological and chemical evaluations of 3-chloro-2-oxazolidinones.

Comparative antimicrobial activity of 3-chloro-2-oxazolidinone (I), 3-chloro-4-methyl-2-oxazolidinone (II), 3-chloro-4,4-dimethyl-2-oxazolidinone (III), and N-chlorosuccinimide (IV) was evaluated in aqueous buffers in the absence and presence of 5% horse serum. All four compounds had similar bactericidal activity in the absence of horse serum, but I and III had superior activity relative to IV when serum was present. Compound III was considerably more stable with respect ot loss of positive chlorine and bactericidal activity than I and II when stored in 0.1 M sodium dihydrogen phosphate buffered to pH 7.0 at 40 degrees. Thus, III is potentially the most useful bactericidal agent of those evaluated. The chlorine potentials of I, II, and III, the rate constants for transfer of positive chlorine from I and III to morpholine in aqueous solutions, and the hydrolytic stabilities of I and III with respect to loss of positive chlorine were evaluated. These data, together with previously calculated data for IV, are used to rationalize the observed bactericidal activities.

Solubilization and stabilization of the cytotoxic agent coralyne.

Kinetic studies were carried out on the ring opening of the quaternary nitrogen cation, coralynium ion (I), to yield 6'-acetylpapaverine (III), on the cyclization of III to yield I, and on a photochemical reaction undergone by I in aqueous solutions exposed to visible light. From the results, it was concluded that: (a) I and III are in facile equilibrium in aqueous solution but appreciable amounts of III do not exist in dilute solutions with pH values below 10: (b) the photochemical reaction of I in water (presumably a photohydration) can be reversed by lyophilization, by heatiing, and by increasing the pH of solutions to values greater than 12; (c) the photochemical reaction of I can be inhibited by protecting the aqueous solutions from visible light, and the rate in the presence of light can be reduced by increasing the concentration of I in the solution; and (d) although the chloride and sulfoacetate salts of I react identically and have similar solubilities in water, it is possible to prepare more concentrated and, hence, more stable solutions of the sulfoacetate salt by including sodium hydroxide in the solvent. The solubility of coralyne chloride remains about the same in dilute sodium hydroxide as in water.